Efficacy of Topical Azithromycin versus Systemic Doxycycline in Treatment of Meibomian Gland Dysfunction

Background Ocular surface disease (OSD) is a multifactorial and highly frequent problem. Inadequate or unstable tear film is the main cause, which leads to visual impairments. One of the primary causes of OSD is meibomian gland dysfunction (MGD), with a prevalence of 3.5 to 70%. The aim of this work was to compare the efficacy of azithromycin topical eye drops versus oral doxycycline in MGD individuals. Methods This prospective comparative cohort research was carried out on 56 patients of both sexes of any age with symptomatic MGD. Randomly, patients were classified into two equal groups: Group 1 was treated twice daily for 4 weeks with topical azithromycin 1% eye drops, while group 2 received oral doxycycline 100 mg capsules twice daily for 4 weeks. Results In the 1st follow-up, there was a significant difference between the studied groups in pain and discomfort degree (P value = 0.024) as group 1 showed a higher number of patients with a mild pain degree (P value = 0.013) while group 2 showed a higher number of patients with a severe pain degree (P value = 0.022). There was an insignificant difference between the studied groups in moderate pain degree and lid margin telangiectasia. Conjunctivitis, frothy discharge, and meniscus floaters were significantly higher in group 2 than in group 1 (P value = 0.013, 0.028, and 0.031, respectively). In group 1, the break-up time test was significantly higher than in group 2 (P value = 0.023). In the 2nd follow up, in group 2 only meniscus floaters were significantly higher than in group 1 (P value = 0.044), while in group 1 break-up time test was significantly higher than in group 2 (P value = 0.029). Otherwise, there is no significant difference between both the groups. Conclusions Meibomian gland dysfunction (MGD) could be treated effectively with oral doxycycline and topical azithromycin by improving symptoms, clinical signs, and stabilization of tear film. Moreover, the topical azithromycin group seemed to be superior over the oral doxycycline group in improving the quality of tear film in the short term, having fewer side effects, more compliance, and better tolerability.


Introduction
Ocular surface disease (OSD) is a multifactorial and a highly frequent problem which may lead to pain, infammation, irritation, photophobia, blurred vision, and vision loss [1]. Tere are many essential causes of OSD such as inadequate or unstable tear flm and neurotrophic keratopathy (NK) which is a degenerative corneal disorder that afects the health and integrity of the ocular surface secondary to impairment of corneal nerves that alters their trophic and sensory function [2]. Also, meibomian gland dysfunction (MGD) incidence varies widely from 3.5 to 70% based on ethnicity, sex, and age. MGD also has a signifcant infuence on the patients' life quality, as it is frequently a contributing factor to evaporative dry eye and is responsible for symptoms of irritation of the eyelid and ocular surface. [3].
Risk factors of MGD include aging, defciency of sex hormones specially androgens, other systemic diseases such as Stevens-Johnson syndrome (SJS), atopy, Sjogren's syndrome (SS), psoriasis, and hypertension. Also, ophthalmic disorders such as chronic blepharitis, contact lens wear, and trachoma may play a role. Demodex folliculorum infestation and aniridia have been shown to afect meibomian gland function. Te use of antibiotics, isotretinoin for acne, antihistamines, antidepressants, and hormone replacement therapy has been found to be associated with MGD [3,4]. MGD pathophysiology is caused by obstruction of meibomian gland and hyper-keratinization of the epithelium of the meibomian duct which results in decreased meibum availability over the tear flm aqueous layer. Reduced meibum leads to elevation of bacterial growth on the margin of the lid, instability of the tear flm, increased hyperosmolarity, and tears evaporation [4]. MGD choices of treatment vary from initial conservative interventions involving eyelid massage, eyelid expression, and warm compression to, in more severe cases, medical intervention with anti-infammatory drugs. In past trials, antibiotics such as doxycycline and azithromycin were proven to efectively treat both the signs and symptoms of MGD patients [5].
Doxycycline is one of the standard treatments for MGD, which is a derivative of tetracycline and has been used because of its lipid-regulating, anti-infammatory, and antimicrobial characteristics. It suppresses matrix metalloproteinases, which are responsible for connective tissue degradation. It has been used to treat ocular rosacea by alleviating symptoms of irritation and increasing the stability of the tear flm. In addition, it has been used to cure erosions of the cornea [6].
Topical azithromycin has been identifed as a potentially well-tolerated and efective treatment for MGD and diseases of the lid margin in clinical trials. Azithromycin is a macrolide antibiotic that has a broad-spectrum action, antiinfammatory characteristics, and a lipid-regulating efect. In addition, at concentrations achieved by topical administration, it displayed bacteriostatic activity, resulting in the bacterial growth suppression on the lid margin [7].
Tis work aimed to compare topical azithromycin eye drops versus oral doxycycline efcacy in MGD patients.

Patients and Methods
Tis comparative prospective cohort study was carried out on 56 patients of both the sexes, of any age who presented with symptomatic MGD. It was done in the Ophthalmology Department Menoufa University Hospital from September 2020 to September 2021.
An informed written consent was obtained from the patient or relatives of the patient. Te study was done after approval from the Ethics Committee Menoufa University Hospitals (19819OPHT23).
Exclusion criteria were history of any ocular surface surgery (including pterygium resection and refractive surgeries), ocular injuries, pregnant and lactating women, women on oral contraceptive pills, a known hypersensitivity to azithromycin or doxycycline, contact lens wearing, gross lid structural abnormality, and corneal scarring. Te use of any of the following medications within one month of the study: ocular or oral antibiotics, topical or systemic steroids, ocular nonsteroidal anti-infammatory drugs, topical cyclosporine, topical antihistamine, and/or mast cell stabilizers.
All patients were subjected to personal history taking and a thorough ophthalmic examination involving (measurement of visual acuity, manifest refraction, and slit lamp biomicroscopy).
Patients with MGD were randomly (by computerassisted program) and equally divided into two groups. Group 1 was treated twice daily for 4 weeks with topical Cyanaro (azithromycin 1%) eye drops (Talent Pharma Group, New Cairo, Egypt) and group 2 received oral vibramycin (100 mg doxycycline) capsules (Pfzer, Cairo, Egypt) twice daily for 4 weeks. Te two groups were maintained on conservative management in the form of eyelid massage, cleaning using eye-friendly soap at bedtime (Baby Johnson Shampoo, Johnson & Johnson), warm fomentation twice daily, and artifcial tear eye drop Systane Ultra (Alcon Laboratories, Fort Worth, Texas, USA) 4 times daily. Te data were collected: On admission, after 2 weeks (frst follow-up) and after 4 weeks (second followup), and the parameters were compared between both groups.
Pain assessment was done according to the Wong and Baker Face Pain Scale which was created by Donna Wong and Connie Baker. Te scale depicts a faces sequence fuctuating from a crying face at 10, which indicates "hurts like the worst pain imaginable to a happy face at 0, which indicates "no hurt." According to the written descriptions and faces, the patient chooses the face that most closely fts their pain level. In our study, the Wong and Baker pain scale was categorized into three degrees: (severe pain: 7-10, moderate pain: 4-6, and mild pain: 1-3).
As regards the lid margin telangiectasia scale, the grading scale is dependent on defnite properties. Abnormal vascularity fndings of the lid margin are dependent on 2 major components: the distribution of telangiectasia crossing meibomian gland orifces and the lid margin redness degree. 0 � no or slight redness in the lid margin conjunctiva and no telangiectasia crossing meibomian gland orifces.
1 � redness in the lid margin conjunctiva and no telangiectasia crossing meibomian gland orifces.
2 � redness in the lid margin conjunctiva and telangiectasia crossing meibomian gland orifces with a distribution of less than half of the full length of the lid.
3 � redness in the lid margin conjunctiva and telangiectasia crossing meibomian gland orifces with a distribution of half or more of the full length of the lid.
Also, we assessed the presence or absence (positive or negative) of conjunctivitis, frothy discharge, and tear flm meniscus foaters.
Break-up Time Test: It is a clinical examination that is used to diagnose evaporative dry eye disease. Te patient's tear flm is instilled with fuorescein for TBUT measurement, and the patient is urged not to blink while the tear flm is detected by a broad beam of cobalt blue illumination.
Following a time interval, lines or black spots appear in the fuorescein-stained flm, indicating the establishment of dry patches. Te time interval between the fnal blink and the emergence of the frst dry spot is referred to as the TBUT. A TBUT shorter than ten seconds is seen as abnormal.

Statistical
Analysis. SPSS v26 (IBM Inc., Chicago, IL, USA) was used to perform statistical analysis. Quantitative variables were presented as the mean and standard deviation (SD) and utilize unpaired Student's t-test to compare the two groups. Qualitative data were presented as frequency and percentage (%), and chi-square test or Fisher's exact test when appropriate were used in their analysis. Te level of signifcance for all tests was set at P < 0.05.

Results
Tere was an insignifcant diference between both groups in age and gender. (Table 1) Pain and discomfort, lid margin telangiectasia, conjunctivitis, frothy discharge, meniscus foaters, and break-up time tests in the 1 st visit were insignifcantly diferent between both groups. (Table 2) In the 1 st follow-up, there was a signifcant diference between the studied groups in pain and discomfort degree (P value � 0.024). Patients with mild pain degrees were signifcantly higher in the topical azithromycin group (P value � 0.013), and patients with severe pain were signifcantly higher in the systemic doxycycline group (P � 0.022). Tere was an insignifcant diference between the studied groups in moderate pain degree and lid margin telangiectasia. Conjunctivitis and meniscus foaters were signifcantly lower in the topical azithromycin group than in the systemic doxycycline group (P value � 0.013, 0.031, respectively). Break-up time tests and patients with negative frothy discharge were signifcantly higher in the topical azithromycin group than in the systemic doxycycline group (P � 0.023, 0.028, respectively). (Table 3) In the 2 nd follow-up, pain and discomfort, lid margin telangiectasia, conjunctivitis, and frothy discharge were insignifcantly diferent between the studied groups. Meniscus foaters in the 2 nd follow-up were signifcantly lower in the topical azithromycin group than in the systemic doxycycline group (P value � 0.044), while break-up time test was signifcantly higher in the topical azithromycin group (P value � 0.029). (Table 4) With regards to side efects in both groups, burning sensation was signifcantly higher in the topical azithromycin group (P � 0.023) and GIT upset was signifcantly higher in the systemic doxycycline group (P < 0.001). Absence of any side efects, stinging sensation, sticky eyelids, photosensitivity, and allergic reaction were insignifcantly diferent between the two groups.

Discussion
Obstructive MGD is the most prevalent cause of EDE and occurs as a primary disorder or secondary to seborrheic or atopic dermatitis, acne rosacea, and cicatrizing conjunctival disorders, such as erythema multiforme, trachoma, and cicatricial pemphigoid [8].
Te main goal of the treatment of MGD is to improve the quality and quantity of meibomian glands secretion and thus relieve discomfort. Many studies have shown the essential role of eyelid warming and massaging and topical antibiotics such as macrolides and tetracycline in the treatment of MGD. Recent studies demonstrated intense pulsed light (IPL) efcacy can enhance manifestations in patients with dry eye disorder (DED) and MGD. However, the exact mechanisms of action are still not completely clear, the thermal efect produced by a series of pulses of noncoherent polychromatic light results in the liquefaction of meibum, reducing proinfammatory mediators and matrix metalloproteinases' production. Furthermore, low-level light therapy (LLLT), using light-emitting diodes (LEDs) at wavelengths insufcient to create a thermal efect, has shown good results in dermatology through a mechanism of action known as photobiomodulation [9].
Antibiotics such as lymecycline and azithromycin all help reduce dry eye symptoms because of their antiinfammatory action. Tere are a surprisingly large number of antibiotics that have a concomitant anti-infammatory action which we can use as an important treatment for dry eye disease due to meibomian gland dysfunction. Te action is twofold in that they alter, reduce, or alter the eyelid fora, and the microbiome that is contributing to the meibomian gland dysfunction alters the ocular surface infammation through their direct anti-infammatory efect. Full doses do not have to be taken, and small doses can be used for a longer period of time. Te two main groups of antibiotics that we use are tetracyclines and macrolides. Oral doxycycline, minocycline, or lymecycline successfully improve symptoms and signs of meibomian gland dysfunction. However, there are some potential gastrointestinal side efects. Tere is also some concern about whether they will afect the gut microbiome. For instance, it is not totally clear what longterm efects doxycycline or lymecycline have on altering the gut fora and how, therefore, the gut microbiome may modulate the body's immune system. An alternative is to use azithromycin either topically, orally, or both [5,8].
Our study assessed the efcacy of topical azithromycin versus systemic doxycycline in the treatment of meibomian gland dysfunction. We reported insignifcant diferent results regarding the pain and discomfort, lid margin telangiectasia, and conjunctivitis between both studied groups in the frst visit.
Regarding pain and discomfort, a long-term, randomized study conducted by De Benedetti and Vaiano [8] compared doxycycline (4 g for 30 days) and oral azithromycin (1.25 g for 5 days) in MGD patients for 9 months and discovered comparable results to ours as both groups showed an insignifcant diference in pain degree in the frst visit. Tey also reported that there was no signifcant difference between the doxycycline and azithromycin group in conjunctivitis. Concerning the lid margin telangiectasia, our results are similar to those of Foulks et al. [10] who demonstrated that there was no signifcant diference was recorded between the doxycycline and azithromycin group regarding lid margin telangiectasia.
In addition, the present results revealed that there was no signifcant diference observed between the azithromycin and doxycycline groups with respect to frothy discharge and meniscus foaters in the frst visit. Our fndings are in accordance with Hamed et al. [11] who assessed their comparative study to compare the outcome of using topical Journal of Ophthalmology azithromycin and doxycycline in improving signs and symptoms of posterior blepharitis causing MGD. One hundred and twenty eyes of sixty patients of both sexes above the age of 18 diagnosed with posterior blepharitis causing dry eye disease were enrolled. Te results showed that in the frst visit, the frothy discharge between groups was insignifcantly diferent.
Moreover, concerning the frst visit, the break-up time test was insignifcantly diferent between both groups. Our results agree with Foulks et al. [10] who reported that the break-up time of tear of patients with MGD was statistically nonsignifcant between azithromycin and doxycycline groups in admission time.
Our results demonstrated that in the frst follow-up there was a signifcant diference between the studied groups in pain and discomfort degrees. Te number of patients with mild pain degrees was signifcantly higher in the group of topical azithromycin and the number of patients with severe  Data are presented as mean ± SD. Data are presented as mean ± SD, * : signifcant as P value ≤ 0.05.
pain was signifcantly higher in the systemic doxycycline group. Tere was an insignifcant diference between the studied groups in moderate pain degree. Similarly, Kashkouli et al. [5] showed that signs and symptoms in both groups had improved after 60 days of treatment, but the overall symptoms in the azithromycin group, including pain degree and signs, decreased to a mild score. Te reduction in symptoms, pain degree, and signs was more signifcant in the azithromycin group compared to the doxycycline group. Furthermore, our study demonstrated that the lid margin telangiectasia in 1 st follow-up was insignifcantly diferent between the studied groups. Our results are against Kashkouli et al. [5] who found that in the frst follow-up of patients, there was a signifcant decrease in lid margin telangiectasia in the azithromycin group compared to the doxycycline group. Te limited sample size of our study may account for this diference.
Besides, the obtained results explained that the conjunctivitis in 1 st follow-up after 2 weeks of treatment was signifcantly lower in the topical azithromycin 6 (21.43%) than systemic doxycycline 15 (53.57%). Te results recorded by Foulks et al. [10] matched with ours where the conjunctivitis in 1 st follow-up after 1 week was signifcantly lower in topical azithromycin 1.10 ± 0.88 than systemic doxycycline 1.57 ± 0.73.
Moreover, our recorded data showed that in the 1 st follow-up, patients with negative frothy discharge were signifcantly higher in the topical azithromycin group than in the systemic doxycycline group. Our results disagree with Hamed et al. [11] who demonstrated that the signs of 1 st follow-up after 1 week showed a nonsignifcant diference between the azithromycin group and the doxycycline group in frothy discharge. Te short follow-up and the diferent sample sizes led to the diference in outcomes between our and Hamed et al. studies.
Furthermore, the meniscus foaters in 1 st follow-up of our fndings were signifcantly lower in topical azithromycin than systemic doxycycline. Similar results were reported by Lam et al. [12] who conducted, in 2020, a systematic review of the recent publications concerning MGD treatment options. A total of 35 articles were examined for relevance. Generally, all treatment modalities were clinically efcient in reducing dry eye signs and symptoms; however, the degree of improvement and persistence of efects varied between the diferent treatments.
In addition, our results showed that in the 1 st follow-up, the break-up time test was signifcantly higher in the topical azithromycin group. Tese results are in agreement with Hamed et al. [11] who demonstrated that in the frst followup for the azithromycin group and the doxycycline group the tear break-up time was signifcantly increased in azithromycin-treated patients compared to the doxycycline group.
Besides, the present research results illustrated that pain and discomfort, lid margin telangiectasia, and conjunctivitis in the 2 nd follow-up were insignifcantly diferent between studied groups.
Tese fndings are comparable to those of Satitpitakul et al. [13] who carried out a prospective randomized trial to evaluate the efcacy of azithromycin 1.5% eyedrops in individuals with moderate to severe MGD when compared to oral doxycycline. Newly diagnosed moderate-to-severe MGD in 169 cases were involved. 85 patients were randomly assigned to receive azithromycin 1.5% eyedrops twice daily for two days and then once daily for four weeks, and 84 patients received oral doxycycline 100 mg twice daily for four weeks. Symptoms and signs of MGD were assessed later at the baseline and after 4 weeks. Te results explained that after 4 weeks of follow-up, MGD-related symptoms including discomfort symptom was shown in 54 (75.00%) patients in the azithromycin group compared to 55 (78.57%) patients in the doxycycline group.
Moreover, Foulks et al. [10] reported a similar result: all signs of the disease of the eyelid margin including telangiectasia alleviated after 4 weeks follow-up in both groups Data are presented as mean ± SD, * : signifcant as P value ≤ 0.05.
Journal of Ophthalmology with no statistically signifcant diference between azithromycin and doxycycline groups. In addition, De Benedetti and Vaiano [8] showed a similar result in 2 nd follow-up as there was no statistically signifcant diference between both groups concerning the conjunctivitis.
Likewise, another major fnding in the second follow-up was that the frothy discharge was insignifcantly diferent between the investigated groups.
Moreover, this result was consistent with Fadlallah and colleagues [14] who carried out a study to evaluate topical 1.5% azithromycin efcacy in chronic blepharitis of moderate-to-severe degree treatment and to compare the efcacy of two diferent treatment modalities. 67 patients with chronic anterior and/or posterior blepharitis resulting in dry eyes were included in a randomised clinical trial and observed for three months. Symptoms and signs were graded based on the severity. Patients were randomly assigned into two groups: Group I received for three days 1.5% azithromycin topically twice daily; Group II received 1.5% azithromycin topically twice daily for three days followed by bedtime treatment for the remainder of the month.
Te results showed insignifcant improvement in frothy discharge, and this may be due to the fact that azithromycin could not reach the therapeutic level on the meibomian gland to stabilize the tear flm.
Interestingly, our results indicated that in the 2 nd followup, the break-up time test was signifcantly higher in the topical azithromycin group. Tese results matched with those of Foulks et al., [10] who demonstrated that in the 2 nd follow-up after 4 weeks for azithromycin-treated patients and 8 weeks for doxycycline treated patients, the tear breakup time was signifcantly higher in patients treated with azithromycin compared to the doxycycline group.
Also, a better understanding of healthy eye microbiota has the potential to improve disease diagnosis and personalized regimens to promote health. [15].

Limitations.
Te sample size of this study was relatively small, there was a short follow-up period, and it was a singlecentric study. Also, we did not conduct the various tests of visual function such as contrast sensitivity test and colour vision tests.

Conclusions
Meibomian gland dysfunction (MGD) could be treated efectively with oral doxycycline and topical azithromycin by improving symptoms, clinical signs, and stabilization of the tear flm. Moreover, topical group seemed to be superior over oral group in improving the quality of the tear flm in the short term, with fewer side efects, more compliance, and better tolerability.

Data Availability
Te datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Ethical Approval
Tis study was approved by Ethical Committee of the Menoufa University Hospital, all patients received a thorough explanation of the study design and aims followed by a signed informed consent. Te study was conducted in compliance with the tenets of the Declaration of Helsinki.

Conflicts of Interest
Te authors declare that they have no conficts of interest.